US3541085A - Method of preparing thiotricyclic compounds - Google Patents
Method of preparing thiotricyclic compounds Download PDFInfo
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- US3541085A US3541085A US823510A US3541085DA US3541085A US 3541085 A US3541085 A US 3541085A US 823510 A US823510 A US 823510A US 3541085D A US3541085D A US 3541085DA US 3541085 A US3541085 A US 3541085A
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- 238000000034 method Methods 0.000 title description 18
- 150000001875 compounds Chemical class 0.000 title description 16
- -1 aminodibenz[b,f][1,4]oxazepines Chemical class 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- 241001061127 Thione Species 0.000 description 15
- 229920000137 polyphosphoric acid Polymers 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000013078 crystal Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 125000003282 alkyl amino group Chemical group 0.000 description 6
- KOSYAAIZOGNATQ-UHFFFAOYSA-N o-phenyl chloromethanethioate Chemical compound ClC(=S)OC1=CC=CC=C1 KOSYAAIZOGNATQ-UHFFFAOYSA-N 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000000935 antidepressant agent Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 4
- 230000001430 anti-depressive effect Effects 0.000 description 4
- 230000037023 motor activity Effects 0.000 description 4
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000021824 exploration behavior Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- FWULFEHVLSQUBD-UHFFFAOYSA-N phenyl n-(2-phenylsulfanylphenyl)carbamate Chemical compound C=1C=CC=CC=1OC(=O)NC1=CC=CC=C1SC1=CC=CC=C1 FWULFEHVLSQUBD-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229960005333 tetrabenazine Drugs 0.000 description 3
- 230000002936 tranquilizing effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DGBISJKLNVVJGD-UHFFFAOYSA-N 2-phenylsulfanylaniline Chemical compound NC1=CC=CC=C1SC1=CC=CC=C1 DGBISJKLNVVJGD-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000000221 oxazepines Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000003204 tranquilizing agent Substances 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- WXLCDTBTIVJDCE-UHFFFAOYSA-N 1,4-oxazepine Chemical compound O1C=CC=NC=C1 WXLCDTBTIVJDCE-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- HUOAUSKBMZADON-UHFFFAOYSA-N 11h-benzo[b][1,4]benzodiazepin-7-amine Chemical class N1C2=CC=CC=C2N=CC2=C1C=CC=C2N HUOAUSKBMZADON-UHFFFAOYSA-N 0.000 description 1
- QKKBREBZMUFUDS-UHFFFAOYSA-N 2-(4-chlorophenoxy)aniline Chemical compound NC1=CC=CC=C1OC1=CC=C(Cl)C=C1 QKKBREBZMUFUDS-UHFFFAOYSA-N 0.000 description 1
- DWOBGCPUQNFAFB-UHFFFAOYSA-N 2-benzylaniline Chemical compound NC1=CC=CC=C1CC1=CC=CC=C1 DWOBGCPUQNFAFB-UHFFFAOYSA-N 0.000 description 1
- PUSPDVXRRIWYJW-UHFFFAOYSA-N 2-n-methyl-2-n-phenylbenzene-1,2-diamine Chemical compound C=1C=CC=C(N)C=1N(C)C1=CC=CC=C1 PUSPDVXRRIWYJW-UHFFFAOYSA-N 0.000 description 1
- NMFFUUFPJJOWHK-UHFFFAOYSA-N 2-phenoxyaniline Chemical compound NC1=CC=CC=C1OC1=CC=CC=C1 NMFFUUFPJJOWHK-UHFFFAOYSA-N 0.000 description 1
- XKZSVFMALMPFHB-UHFFFAOYSA-N 4-methyl-n-phenylpiperazine-1-carbothioamide Chemical compound C1CN(C)CCN1C(=S)NC1=CC=CC=C1 XKZSVFMALMPFHB-UHFFFAOYSA-N 0.000 description 1
- RIEQPYFIRMWZRX-UHFFFAOYSA-N 5-chloro-2-phenylsulfanylaniline Chemical compound NC1=CC(Cl)=CC=C1SC1=CC=CC=C1 RIEQPYFIRMWZRX-UHFFFAOYSA-N 0.000 description 1
- JDGIOVSBPLDWSM-UHFFFAOYSA-N 5h-benzo[b][1,4]benzothiazepine-6-thione Chemical compound S=C1NC2=CC=CC=C2SC2=CC=CC=C12 JDGIOVSBPLDWSM-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- FULZLIGZKMKICU-UHFFFAOYSA-N N-phenylthiourea Chemical compound NC(=S)NC1=CC=CC=C1 FULZLIGZKMKICU-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001538 azepines Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000004908 diazepines Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229910052736 halogen Chemical group 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- PMYMYVBNBAVIRT-UHFFFAOYSA-N n-phenylmorpholine-4-carbothioamide Chemical compound C1COCCN1C(=S)NC1=CC=CC=C1 PMYMYVBNBAVIRT-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- 150000004912 thiazepines Chemical class 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D267/20—[b, f]-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D281/16—[b, f]-condensed
Definitions
- the reaction is usually performed using an excess of polyphosphoric acid at a temperature of about 70-200 C. for approximately 15 minutes to 24 hours.
- the preferred temperature is from 100150 C.
- the products (I) are generally obtained by addition of the reaction solution to water.
- the products (I) may be isolated by filtration or extraction with an organic solvent, such as diethyl ether, methylene chloride, and the like.
- the compounds prepared by the novel process of this invention are useful as intermediates for the preparation of 11 substituted aminodibenz[b,f][1,4]oxazepines, 11- substituted aminodibenz[b,f][1,4]thiazepines, 11 -substituted aminodibenz[b,f][1,4]diazepines and 6-substituted aminomorphanthridines.
- the former compounds may be treated with an alkyl halide, aralkyl halide, alkyl sulfonate ester or aralkyl sulfonate ester to give S-alkyl and S-aralkyl derivatives (III).Treatment of compounds (III) with an amine produces the substituted amino derivatives (II) as shown below:
- R and Z are as described hereinbefore and R and R are members of the group consisting of hydrogen, alkyl, alkenyl, aryl, (di-lower alkylamino)alkyl, hydroxyalkyl, and
- piperazino N-lower alkyl piperazino, N-(w-hydroxy lower alkyl)piperazino, N-[(w di lower alkylamino)alkyl1piperazino, morpholino, and cyclopolymethyleneimino of from 4 to 6 carbon atoms, and R is lower alkyl or phenyl lower alkyl.
- the substituted amino derivatives (II) are physiologically active on the central nervous system. They show high activity as tranquilizers at non-toxic doses, and in some instances anti-depressant properties at dosage levels which produce neither overt stimulation nor depression.
- a useful test for tranquilizer activity consists of meas- 0 uring the reduction of spontaneous motor activity in animals by means of an actophotometer (a photoelectric device for quantitatively measuring locomotor activity).
- Graded doses of the active compounds (II) are administered to groups of mice, and the effective dosage range for a significant reduction of motor activity (a measure of tranquilization) compared to control groups is established.
- the use of reduced motor activity as a measure of tranquilizing activity has been described by W. D. Gray, A. C. Osterberg and C. E. Rauh, Archives Internationales et de Therapie, vol. 134, p. 198 (1961) and by W. J. Kinnard and C. J. Carr, Journal of Pharmacology and Experimental Therapeutics, vol. 121, p. 354 (1957).
- the anti-depressant properties of the compounds (II) are evident by measuring their ability to counteract a depression induced in animals by the administration of tetrabenazine hexamate.
- Graded doses of the active compounds (II) are administered to groups of mice, and this is followed by administering a dose of tetrabenazine which is known to markedly depress the exploratory behavior of normal mice.
- the anti-depressant treated groups show normal exploratory behavior, while the control groups, and groups treated with an ineffective anti-depressant agent, do not show this normal exploratory behavior, but show the well known profound depression induced by tetrabenazine.
- the results from several dose levels are used to establish effective dose ranges.
- the anti-depressant compounds (II) show their desirable properties by this procedure at dose levels which produce little or no untoward reactions such as ataxia or reduced spontaneous motor activity.
- 2-benzyl-4-methyl-1-piperazinethiocarboxanilide 500 mg. is heated in polyphosphoric acid (about ml.) for 15 minutes at 125-135 C., whereafter the mixture is poured into ice-water and stirred until the polyphosphoric acid is dissolved. The solution is extracted three times with ether, and the extracts dried over potassium carbonate and evaporated to give a residue that crystallizes upon trituration with ether. Recrystallization from methanol and then from ethyl acetate gives 5,6-dihydromorphanthridine-G-thione as yellow needles, melting point 221- 233 C.
- EXAMPLE 4 Preparation of 5,6-dihydromorphanthridine-6-thione
- treatment of phenyl 2-benzylthiocarbanilate with polyphosphoric acid at 100 C. for one hour gives the product as yellow needles, melting point 220-223 C.
- EXAMPLE 8 Preparation of 10,1 l-dihydro-S-methyldibenz [b,f] 1,4]diazepine-l l-thione
- phenyl 2 (N methylanilino)thiocarbanilate which is obtained as an oil.
- phenyl 2- (N-methylanilino)thiocarbanilate, prepared above is treated with l-methylpiperazine, crystals of 4 methyl-2-(N-methylanilino) 1 piperazinethiocarboxanilide, melting point 131-132 C., result.
- EXAMPLE 10 Preparation of 2 chloro-10,11-dihydrodibenz[b,f] [1,4] oxazepine-l l-thione 6
- EXAMPLE 11 Preparation of 2 chloro-10,11-dihydrodibenz[b,f][1,4] oxazepine-l l-thione
- EXAMPLE 12 Preparation of 2 chloro-10,11-dihydrodibenz[b,f][1,4] oxazepine-l l-thione
- R is selected from the group consisting of hydrogen and halogen and Z is selected from the group consistmg of oxygen, sulfur, methylene and N-lower alkyl,
- W is selected from the group consisting of phenoxy, dilower alkyl amino, N lower alkylpiperazino, N (w hydroxy lower alkyl)piperazino, N [(w dilower alkylamino)lower alkyl]piperazino, morpholino, cyclopolymethyleneimino of 4 to 6 carbon atoms with polyphosphoric acid at a temperature of from about 70 C. to 200 C. for a period of form about 15 minutes to about 24 hours and recovering said compound therefrom.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
U.S. Cl. 260-2393 United States Patent Oflice 3,541,085 METHOD OF PREPARING THIOTRICYCLIC COMPOUNDS Richard Moats Sheeley, Shippensburg, Pa., and George Rodger Allen, Jr., Old Tappan, N.J., assignors to American Cyanamid Company, Stamford, Conn., 21 corporation of Maine No Drawing. Continuation-impart of application Ser. No. 602,147, Dec. 16, 1966. This application May 9, 1969, Ser. No. 823,510
Int. Cl. C07d 53/00, 93/42, 87/54 10 Claims ABSTRACT OF THE DISCLOSURE This invention describes the preparation of oxazepines, thiazepines, diazepines and azepines. These compounds are prepared by condensing intermediates such as substituted thiocarbanilates or thioureas with an excess of polyphosphoric acid .to produce dibenz heterocyclicthiones. The present compounds are intermediates for preparing compounds having physiological activity at the central nervous system.
This application is a continuation-in-part of application Ser. No. 602,147, filed Dec. 16, 1966, now abandoned. Starting materals used in this application are de scribed and claimed in application Ser. No. 602,149, also filed Dec. 16, 1966, now abandoned.
DESCRIPTION OF THE INVENTION The compounds prepared by the novel process of this invention may be represented by the following formula:
phosphoric acid as illustrated in the following reaction scheme:
S H (J-W NH R Polyphosphoric Acid Z r S I N I wherein R and Z are as described hereinbefore and W is selected from the group consisting of mononuclear aryloxy, di-lower alkyl amino, N-lower alkylpiperazino, N-(w- 3,541,085 Patented Nov. 17, 19 70 hydroxy lower alkyl)piperazino, N-[(w-dilower alkylamino)lower alkyl]piperazino, morpholino, cyclopolymethyleneimino of from 4 to 6 carbon atoms.
The reaction is usually performed using an excess of polyphosphoric acid at a temperature of about 70-200 C. for approximately 15 minutes to 24 hours. The preferred temperature is from 100150 C. When the desired cyclization has been achieved, the products (I) are generally obtained by addition of the reaction solution to water. The products (I) may be isolated by filtration or extraction with an organic solvent, such as diethyl ether, methylene chloride, and the like.
The compounds prepared by the novel process of this invention are useful as intermediates for the preparation of 11 substituted aminodibenz[b,f][1,4]oxazepines, 11- substituted aminodibenz[b,f][1,4]thiazepines, 11 -substituted aminodibenz[b,f][1,4]diazepines and 6-substituted aminomorphanthridines. Thus, in accord with the following reaction scheme, treatment of the compounds (I), prepared by the process of this invention, with an amine gives the ll-substituted aminodibenz[b,f] [1,4] oxazepines, ll-substituted aminodibenz[b,f] [1,4]thiazepines, 11 substituted aminodibenz[b,f][1,4]diazepines or 6-substituted aminomorphanthridines (II). Alternatively, for the conversion of (I) into (II) the former compounds may be treated with an alkyl halide, aralkyl halide, alkyl sulfonate ester or aralkyl sulfonate ester to give S-alkyl and S-aralkyl derivatives (III).Treatment of compounds (III) with an amine produces the substituted amino derivatives (II) as shown below:
(III) wherein R and Z are as described hereinbefore and R and R are members of the group consisting of hydrogen, alkyl, alkenyl, aryl, (di-lower alkylamino)alkyl, hydroxyalkyl, and
taken together are piperazino, N-lower alkyl piperazino, N-(w-hydroxy lower alkyl)piperazino, N-[(w di lower alkylamino)alkyl1piperazino, morpholino, and cyclopolymethyleneimino of from 4 to 6 carbon atoms, and R is lower alkyl or phenyl lower alkyl.
The substituted amino derivatives (II) are physiologically active on the central nervous system. They show high activity as tranquilizers at non-toxic doses, and in some instances anti-depressant properties at dosage levels which produce neither overt stimulation nor depression.
A useful test for tranquilizer activity consists of meas- 0 uring the reduction of spontaneous motor activity in animals by means of an actophotometer (a photoelectric device for quantitatively measuring locomotor activity). Graded doses of the active compounds (II) are administered to groups of mice, and the effective dosage range for a significant reduction of motor activity (a measure of tranquilization) compared to control groups is established. The use of reduced motor activity as a measure of tranquilizing activity has been described by W. D. Gray, A. C. Osterberg and C. E. Rauh, Archives Internationales et de Therapie, vol. 134, p. 198 (1961) and by W. J. Kinnard and C. J. Carr, Journal of Pharmacology and Experimental Therapeutics, vol. 121, p. 354 (1957).
The anti-depressant properties of the compounds (II) are evident by measuring their ability to counteract a depression induced in animals by the administration of tetrabenazine hexamate. Graded doses of the active compounds (II) are administered to groups of mice, and this is followed by administering a dose of tetrabenazine which is known to markedly depress the exploratory behavior of normal mice. The anti-depressant treated groups show normal exploratory behavior, while the control groups, and groups treated with an ineffective anti-depressant agent, do not show this normal exploratory behavior, but show the well known profound depression induced by tetrabenazine.
The results from several dose levels are used to establish effective dose ranges. The anti-depressant compounds (II) show their desirable properties by this procedure at dose levels which produce little or no untoward reactions such as ataxia or reduced spontaneous motor activity.
In addition, some of the compounds (II) show other valuable pharmaceutical properties such as analgesic activity.
The following examples describe in greater detail the process of this invention.
EXAMPLE 1 Preparation of 5,6-dihydromorphanthridine-6-thione A solution of 2.03 g. of phenoxythiocarbonyl chloride in ml. of ether is added dropwise to a stirred solution of 4.32 g. of 2-aminodiphenylmethane in 90 ml. of ether; the resulting mixture is stirred at room temperature for 3 hours and then filtered. The ethereal filtrate is evaporated, and the residue is recrystallized from methanol to give 3.20 g. of phenyl 2-benzylthiocarbanilate as crystals, melting point 101102 C.
A solution of 4.24 g. of phenyl 2-benzylthiocarbanilate, prepared as described above, in 25 ml. of propyl alcohol is treated with 4.25 g. of N-methylpiperazine in 7 ml. of propyl alcohol. The solution is heated at reflux temperature for 30 minutes and poured into cold water. Filtration affords 2'-benzyl-4-methyl-l-piperazinethiocarboxanilide, which is recrystallized from ethyl acetate to give white crystals, melting point l34138 C.
2-benzyl-4-methyl-1-piperazinethiocarboxanilide (500 mg.) is heated in polyphosphoric acid (about ml.) for 15 minutes at 125-135 C., whereafter the mixture is poured into ice-water and stirred until the polyphosphoric acid is dissolved. The solution is extracted three times with ether, and the extracts dried over potassium carbonate and evaporated to give a residue that crystallizes upon trituration with ether. Recrystallization from methanol and then from ethyl acetate gives 5,6-dihydromorphanthridine-G-thione as yellow needles, melting point 221- 233 C.
EXAMPLE 2 Preparation of 10,11-dihydrodibenz [b,f] [1,4] oxazepine-l l-thione Z-aminodiphenyl ether hydrochloride (16.66 g., 0.075 mole) is converted into the free base by shaking with dilute ammonium hydroxide. The liberated base is extracted into ether, and the ethereal solution is dried over sodium sulfate. This solution is treated with a solution of 6.45 g. (0.0375 mole) of phenoxythiocarbonyl chloride in ether. The resulting solution is magnetically stirred at ambient temperature for about 21 hours; filtration gives white crystals of 2-aminodiphenyl ether hydrochloride. The solvent is removed from the filtrate to give an amber oil that crystallizes from hexane to give 12.4 g. of phenyl o-phenoxythiocarbanilate as crystals, melting point 98.
Treatment of phenyl o-phenoxythiocarbanilate (prepared above) with a molar equivalent of l-methylpiperazine gives the product, 4-methyl-2'-phenoxy-l-piperazinethiocarboxanilide, which forms white crystals, melting point l39-142 C., from dilute ethanol.
In the manner described in Example 1, treatment of 4-methyl-2'-phenoxy-1 piperazinethiocarboxanilide (prepared above) with polyphosphoric acid at -120 C. for 1.5 hours gives the product l0,l1-dihydrodibenz[b,f] [1,41oxazepine-1l thione, melting point 196197 C., after recrystallization from ether.
EXAMPLE 3 Preparation of 2-chloro-10,1l-diphydrodibenz [b,f] [1,4]thiazepine-1l-thione In the manner described in Example 2, treatment of 2- amino-4-chlorodiphenyl sulfide with phenoxythiocarbonyl chloride is productive of phenyl 2-(p-chlorophenylthio) thiocarbanilate, which is obtained as white crystals, melting point 114-115 C. Treatment of phenyl 2-(p-chlorophenylthio)thiocarbanilate, prepared above, with l-methylpiperazine gives 2'- (p-chlorophenylthio -4-methyll-piperazinethiocarboxanilide as an oil. This product is dissolved in methanol and treated with concentrated hydrochloric acid. Addition of ether causes precipation of the 2-(p-chlorophenylthio) 4-methyl-1 piperazinethiocarboxanilide hydrochloride as white crystals, melting point 196-197 C.
In the manner described in Example 1, treatment of 2- (p-chlorophenylthio)-4-methyl-1 piperazinethiocarboxanilide hydrochloride with polyphosphoric acid at 115- C. for about 1 hour gives the product 2-chloro-10, 11- dihydrodibenz[b,f][l,4]thiazepine 11 thione, melting point 264-265 C., after recrystallization from ether.
EXAMPLE 4 Preparation of 5,6-dihydromorphanthridine-6-thione In the manner described in Example 1, treatment of phenyl 2-benzylthiocarbanilate with polyphosphoric acid at 100 C. for one hour gives the product as yellow needles, melting point 220-223 C.
EXAMPLE 5 Preparation of 10,11 dihydrodibenz[b,f] [1,4]oxazepine- 1 l-thione Treatment of phenyl o-phenoxythiocarbanilate with piperidine in refluxing propanol for 40 minutes gives the product, 2'-phenoxy 1 piperidinethiocarboxanilide as white needles, melting point l36 C., after recrystallization from dilute ethanol.
In the manner described in Example 1, treatment of 2- phenoxy 1 piperidinethiocarboxanilide with polyphosphoric acid at 115l30 C. for 1 hour gives the product 10,1 1-dil1ydrodibenz[b,f] [1,4]oxazepine-11-thione as yellow crystals, melting point 197 C.
EXAMPLE 6 Preparation of l0,11-dihydrodibenz[b,f][1,4]thiazepine- 1 l-thione Treatment of an ethereal solution of 2-aminodiphenyl sulfide with phenoxythiocarbonyl chloride furnishes phenyl 2-(phenylthio)thiocarbanilate as white crystals, melting point 8688 C., after recrystallization from ethanol. When phenyl 2-(phenylthio)thiocarbanilate is reacted with diethylamine in propanol, there is obtained crystals of 1,1 diethyl-3-(2-phenylthio)phenyl thiourea, melting point 9698 C., after recrystallization from methanol.
By the procedure of Example 1, treatment of 1,1-diethyl 3 (p-phenylthio)phenylthiourea with polyphosphoric acid at 100-115 C. produces 10,11 dihydrodibenz[b,f] [1,4]thiazepine-11-thione.
EXAMPLE 7 Preparation of 2 chloro-10,11-dihydrodibenz[b,f][1,4] oxazepine-l l-thione In the manner described in Example 2, treatment of 2- amino-4'-chlorodiphenyl ether with phenoxy thiocarbonyl chloride gives phenyl 2-(p-chlorophenoxy)thiocarbanilate as an amber oil. This oil crystallizes after prolonged trituration with water. Recrystallization from heptane furnishes a white solid, melting point 69.57l.0 C. Treatment of phenylZ-(p-chlorophenoxy)thiocarbanilate with morpholine in refluxing propanol for one hour gives 2-(pchlorophenoxy) 4 morpholinethiocarboxanilide, white needles, melting point 145-147 C.
In the manner described in Example 1, treatment of 2'- (p-chlorophenoxy) 4 morpholinethiocarboxanilide with polyphosphoric acid at IOU-120 C. gives the product 2- chloro 10,11 dihydrodibenz[ b,f] [l,4]oxazepine-l1- thione as yellow needles, melting point 211-215 C.
EXAMPLE 8 Preparation of 10,1 l-dihydro-S-methyldibenz [b,f] 1,4]diazepine-l l-thione Treatment of an ethereal solution of 2 amino-N- methyldiphenylamine with phenoxythiocarbonyl chloride furnishes phenyl 2 (N methylanilino)thiocarbanilate, which is obtained as an oil. When phenyl 2- (N-methylanilino)thiocarbanilate, prepared above, is treated with l-methylpiperazine, crystals of 4 methyl-2-(N-methylanilino) 1 piperazinethiocarboxanilide, melting point 131-132 C., result.
In the manner described in Example 1, treatment of 4- methyl 2' (N-methylanilino)-l-piperazinethiocarboxanilide with polyphosphoric acid gives the product 10,11- dihydro-S-methyldibenz[b,f] 1,4] diazepine-l l-thione.
EXAMPLE 9 Preparation of 2-chloro-10,11 dihydrodibenz[b,f] [1,4] oxazepine-l l-thione Treatment of phenyl 2 (p-chlorophenoxy)thiocarbanilate with l-(fi-hydroxyethyl)piperazine in propanol for minutes gives the product 2-(p-chlorophenoxy)-4- (2-hydroxyethyl)-1-piperazinethiocarboxanilide, as white crystals, melting point 155158 C., after recrystallization from ethyl acetate.
In the manner described in Example 1, treatment of 2'- (p-chlorophenoxy) -4- (6 hydroxyethyl l-piperazinethiocarboxanilide with polyphosphoric acid at 1l5130 C. for 2 hours gives the product 2-chloro-l0,1l-dihydrodibenz[b,f][1,4]oxazepine 11 thione, melting point 210-215 C.
EXAMPLE 10 Preparation of 2 chloro-10,11-dihydrodibenz[b,f] [1,4] oxazepine-l l-thione 6 EXAMPLE 11 Preparation of 2 chloro-10,11-dihydrodibenz[b,f][1,4] oxazepine-l l-thione EXAMPLE 12 Preparation of 2 chloro-10,11-dihydrodibenz[b,f][1,4] oxazepine-l l-thione Preparation of 10,11-dihydrodibenz[b,f] 1,4]thiazepine- 1 l-thione A solution of 2.0 g. of 2-(phenylthio)aniline and 860 mg. of phenoxythiocarbonyl cloride in ether is stirred at room temperature for 16 hours. The mixture is filtered, and the ethereal filtrate is evaporated to give phenyl 2- (phenylthio)carbanilate, which is recrystallized from ethanol to give crystals, melting point 8688 C.
In the manner described in Example 1, treatment of phenyl 2-(phenylthio)carbanilate, prepared as described above, with polyphosphoric acid at C. for one hour gives the product 10,11 dihydrodibenz[b,f] [1,4] thiazepine-l l-thione as yellow crystals.
What is claimed is:
1. A method of preparing dibenz heterocyclic thiones of the formula:
r r 'L wherein R is selected from the group consisting of hydrogen and halogen and Z is selected from the group consistmg of oxygen, sulfur, methylene and N-lower alkyl,
wherein R and Z are as described above, and W is selected from the group consisting of phenoxy, dilower alkyl amino, N lower alkylpiperazino, N (w hydroxy lower alkyl)piperazino, N [(w dilower alkylamino)lower alkyl]piperazino, morpholino, cyclopolymethyleneimino of 4 to 6 carbon atoms with polyphosphoric acid at a temperature of from about 70 C. to 200 C. for a period of form about 15 minutes to about 24 hours and recovering said compound therefrom.
2. A method of preparing dibenz heterocyclic thiones according to claim 1, wherein the reaction is carried out at a temperature of from about 70 to 200 C. for a period of from 15 minutes to 24 hours.
3. A method of preparing dibenz heterocyclic thiones according to claim 1, in which the starting material is 2' benzyl 4 methyl-1-piperazinethiocarboxanilide and the product obtained is 5,6 dihydromorphanthridine-6- thione.
4. A method of preparing dibenz heterocyclic thiones according to claim 1, in which the starting material is 2 phenoxy 4 methyl-l-piperazinethiocarboxanilide and the product obtained is 10,11 dihydr0dibenzed[b,f] [1,4] oxazepine-l l-thione.
5. A method of preparing dibenz heterocyclic thiones according to claim 1, in which the starting material is 2' (p chlorophenylthio) 4-methyl-l-piperazinethiocarboxanilide hydrochloride and the product obtained is 2 chloro 10,11 dihydrodibenz[b,f] [1,4]thiazepine-11- thione.
6. A method of preparing dibenz heterocyclic thiones according to claim 1, in which the starting material is phenyl 2 benzylthiocarbanilate and the product obtained is 5,6-dihydromorphanthridine-6-thione.
7. A method of preparing dibenz heterocyclic thiones according to claim 1, in which the starting material is 8 2' phenoxy 1 piperidinethiocarboxanilide and the product obtained is 10,11 dihydrodibenz[b,f][l,4]oxazepine-l l-thione.
8. A method of preparing dibenz heterocyclic thiones according to claim 1, in which the starting material is 2' (p chlorophenoxy) 4-methyl-l-piperazinethiocarboxanilide and the product obtained is 2 chloro 10,11- dihydr0dibenz[b,f] [1,4]0xazepine-1l-thione.
9. A method of preparing dibenz heterocyclic thiones according to claim 1, in which the starting material is phenyl 2 chlorophenoxy)thiocarbanilate and the product obtained is 2 chloro 10,11 dihydrodibenz [b,-f] [1,4]oxazepine-11-thione.
10. A method of preparing dibenz heterocyclic thiones according to claim 1, in which the starting material is phenyl 2 (phenylthio)carbanilat and the product obtained is 10,11 dihydrodibenz[-b,f][1,4]thiazepine-1lthione.
References Cited UNITED STATES PATENTS 3,459,737 8/1969 Schmidt et al 260-2393 HENRY R. J ILES, Primary Examiner R. T. BOND, Assistant Examiner U s. 01. X.R.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82351069A | 1969-05-09 | 1969-05-09 |
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| Publication Number | Publication Date |
|---|---|
| US3541085A true US3541085A (en) | 1970-11-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US823510A Expired - Lifetime US3541085A (en) | 1969-05-09 | 1969-05-09 | Method of preparing thiotricyclic compounds |
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| Country | Link |
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| US (1) | US3541085A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4172831A (en) * | 1974-11-26 | 1979-10-30 | Lilly Industries Limited | Thieno-benzodiazepines |
| EP0419861A3 (en) * | 1989-08-29 | 1992-06-10 | Boehringer Ingelheim Pharmaceuticals Inc. | Dibenz(b,f)(1,4)oxazepin (and thiazepin)-11(10h)-ones and -thiones and their use in the prevention or treatment of aids |
| US5607929A (en) * | 1991-05-02 | 1997-03-04 | Glaxo Wellcome Inc. | Antiviral dibenzothiazepinone derivatives |
| JP2008525397A (en) * | 2004-12-24 | 2008-07-17 | アストラゼネカ・アクチエボラーグ | Heterocyclic compounds as CCR2B antagonists |
| US20100152197A1 (en) * | 2008-12-15 | 2010-06-17 | Astrazeneca Ab | (4-tert-butylpiperazin-2-yl)(piperazin-1-yl)methanone-n-carboxamide derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3459737A (en) * | 1964-04-21 | 1969-08-05 | Boehringer Sohn Ingelheim | Novel 5-substituted 5,6-dihydro-6-oxopyrido(2,3-b) (1,4)benzoxazepines |
-
1969
- 1969-05-09 US US823510A patent/US3541085A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3459737A (en) * | 1964-04-21 | 1969-08-05 | Boehringer Sohn Ingelheim | Novel 5-substituted 5,6-dihydro-6-oxopyrido(2,3-b) (1,4)benzoxazepines |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4172831A (en) * | 1974-11-26 | 1979-10-30 | Lilly Industries Limited | Thieno-benzodiazepines |
| EP0419861A3 (en) * | 1989-08-29 | 1992-06-10 | Boehringer Ingelheim Pharmaceuticals Inc. | Dibenz(b,f)(1,4)oxazepin (and thiazepin)-11(10h)-ones and -thiones and their use in the prevention or treatment of aids |
| JP2862980B2 (en) | 1989-08-29 | 1999-03-03 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレーテッド | Dibenz [b, f] [1,4] oxazepine (and -thiazepine) -11 (10H) -one or -thione pharmaceutical composition for preventing or treating AIDS |
| US5607929A (en) * | 1991-05-02 | 1997-03-04 | Glaxo Wellcome Inc. | Antiviral dibenzothiazepinone derivatives |
| JP2008525397A (en) * | 2004-12-24 | 2008-07-17 | アストラゼネカ・アクチエボラーグ | Heterocyclic compounds as CCR2B antagonists |
| US20110136820A1 (en) * | 2004-12-24 | 2011-06-09 | Astrazeneca Ab | Heterocyclic Compounds as CCR2 Antagonists |
| JP2012214507A (en) * | 2004-12-24 | 2012-11-08 | Astrazeneca Ab | Heterocyclic compound as ccr2b antagonist |
| US20100152197A1 (en) * | 2008-12-15 | 2010-06-17 | Astrazeneca Ab | (4-tert-butylpiperazin-2-yl)(piperazin-1-yl)methanone-n-carboxamide derivatives |
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